Vitamin E

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha (a), beta (b), gamma (g) and delta (d), and four tocotrienols (also a, b, g, and d).

VITAMIN E

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha (a), beta (b), gamma (g) and delta (d), and four tocotrienols (also a, b, g,and d). a-Tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore, the form of vitamin E found in the largest quantities in the blood and tissue (1). Because a-tocopherol is the form of vitamin E that appears to have the greatest nutritional significance, it will be the primary topic of the following discussion. It is also the only form that meets the 2000 RDA for vitamin E.

FUNCTION

Alpha-tocopherol (a-tocopherol): The main function of a-tocopherol in humans appears to be that of an antioxidant. Free radicals are formed primarily in the body during normal metabolism and also upon exposure to environmental factors such as cigarette smoke or pollutants. Fats, which are an integral part of all cell membranes, are vulnerable to destruction through oxidation by free radicals. The fat-soluble vitamin, a-tocopherol, is uniquely suited to intercepting free radicals and preventing a chain reaction of lipid destruction. Aside from maintaining the integrity of cell membranes throughout the body, a-tocopherol also protects the fats in low density lipoproteins (LDLs) from oxidation. Lipoproteins are particles composed of lipids and proteins, which are able to transport fats through the blood stream. LDL transport cholesterol from the liver to the tissues of the body. Oxidized LDLs have been implicated in the development of cardiovascular diseases (See Disease Prevention). When a molecule of a-tocopherol neutralizes a free radical, it is altered in such a way that its antioxidant capacity is lost. However, other antioxidants, such as vitamin C, are capable of regenerating the antioxidant capacity of a-tocopherol (2).

Several other functions of a-tocopherol have been identified, which likely are not related to its antioxidant capacity. a-Tocopherol is known to inhibit the actvity of protein kinase C, an important cell signaling molecule, as well as to affect the expression and activity of immune and inflammatory cells. Additionally, a-tocopherol has been shown to inhibit platelet aggregation and to enhance vasodilation(3,4).

Gamma-tocopherol (g-tocopherol): The function of g-tocopherol in humans is presently unclear. Although the most common form of vitamin E in the American diet is g-tocopherol (see Food Sources), blood levels of g-tocopherol are generally ten times lower than those of a-tocopherol. This phenomenon appears due to the action of the a-tocopherol transfer protein (a-TTP) in the liver, which preferentially incorporates a-tocopherol into lipoproteins that are circulated in the blood (1) and ultimately delivers a-tocopherol to different tissues in the body. See the Linus Pauling Institute Newsletter for more information about a-TTP and vitamin E adequacy. Because g-tocopherol is initially absorbed in the same manner as a-tocopherol, small amounts are detectable in blood and tissue. Products of the metabolism of tocopherols, known as metabolites, can be detected in the urine. More g-tocopherol metabolites are excreted in the urine than a-tocopherol metabolites, suggesting less g-tocopherol is needed for use by the body (5). Limited research in the test tube and in animals indicates that g-tocopherol or its metabolites may play a role in the protection of the body from damage by free radicals (6,7), but these effects have not been convincingly demonstrated in humans. Recently, concern has been raised regarding the fact that taking a-tocopherol supplements lowers g-tocopherol levels in the blood. However, no adverse effects of moderate a-tocopherol supplementation have been demonstrated, while many benefits have been documented (see Disease Prevention and Disease Treatment). In one recent prospective study, increased plasma g-tocopherol levels were associated with a significantly reduced risk of developing prostate cancer, while significant protective associations for increased levels of plasma a-tocopherol and toenail selenium were found only when g-tocopherol levels were also high (8). These limited findings, in addition to the fact that taking a-tocopherol supplements lower g-tocopherol levels in the blood, have led some scientists to call for additional research on the effects of dietary and supplemental g-tocopherol on health (9).

DEFICIENCY

Vitamin E deficiency has been observed in individuals with severe malnutrition, genetic defects affecting the a-tocopherol transfer protein, and fatmalabsorption syndromes. For example, children with cystic fibrosis orcholestatic liver disease, who have an impaired capacity to absorb dietary fat and therefore fat-soluble vitamins, may develop symptomatic vitamin E deficiency. Severe vitamin E deficiency results mainly in neurologicalsymptoms such as impaired balance and coordination, and muscle weakness. The developing nervous system appears to be especially vulnerable to vitamin E deficiency because children with severe vitamin E deficiency from birth, who are not treated with vitamin E, develop neurological symptoms rapidly. In contrast, individuals who develop malabsorption of vitamin E in adulthood may not develop neurological symptoms for 10-20 years. It should be noted that symptomatic vitamin E deficiency in healthy individuals who consume diets low in vitamin E has never been reported (10).

Although true vitamin E deficiency is rare, suboptimal intake of vitamin E is relatively common in the U.S. The National Health and Nutrition Examination Survey III (NHANES III) examined the dietary intake and blood levels of a-tocopherol in 16,295 multi-ethnic adults over the age of 18. Twenty seven % of white participants, 41 % of African Americans, 28% of Mexican Americans and 32% of the other participants were found to have blood levels of a-tocopherol less than 20 mmol/liter, a value chosen because the literature suggests an increased risk for cardiovascular disease below this level (11).

The Recommended Dietary Allowance (RDA):The RDA for vitamin E was previously 8 mg/day for women and 10 mg/day for men. The RDA was revised by the Food and Nutrition Board of the Institute of Medicine in 2000 (3). This new recommendation was based largely on the results of studies done in the 1950s in men fed vitamin E deficient diets. In a test tube analysis, hydrogen peroxide was added to blood samples and the breakdown of red blood cells, known as hemolysis, was used to indicate vitamin E deficiency. Because hemolysis has also been reported in children with severe vitamin E deficiency, this analysis was considered to be a clinically relevant test of vitamin E status. Importantly, this means that the latest RDA for vitamin E continues to be based on the prevention of deficiency symptoms rather than on health promotion and the prevention of chronic disease.

Cardiovascular diseases (heart disease and stroke): The results of at least five large observational studies suggest that increased vitamin E consumption is associated with decreased risk of myocardial infarction (heart attack) or death from heart disease in both men and women. Each study was a prospective study which measured vitamin E consumption in presumably healthy people and followed them for a number of years to determine how many of them were diagnosed with, or died as a result of heart disease. In two of the studies, those individuals who consumed more than 7 mg of a-tocopherol in food were only approximately 35% as likely to die from heart disease as those who consumed less than 3-5 mg of a-tocopherol (12,13). Two other large studies (14,15) found a significant reduction in the risk of heart disease only in those women and men who consumed a-tocopherol supplements of at least 100 IU (67 mg of RRR-a-tocopherol) daily, with the greatest benefit observed at an intake of 800 IU (536 mg RRR-a-tocopherol) daily (16). More recently, several studies have observed plasma or red blood cell levels of a-tocopherol to be inversely associated with the presence or severity of atherosclerosis detected using ultrasonography (17-20). In contrast, intervention studies with vitamin E supplements in patients with heart disease have not shown vitamin E to be effective in preventing heart attacks or death (see Disease Treatment).

Cancer: Many types of cancer are thought to result from oxidative damage to DNA caused by free radicals. The ability of a-tocopherol to neutralize free radicals has made it the subject of a number of cancer prevention studies. However, several large prospective studies have failed to find significant associations between a-tocopherol intake and the incidence of lung cancer or breast cancer (3). A placebo-controlled intervention study designed to look at the effect of a-tocopherol supplementation on lung cancer in smokers found a 34% reduction in the incidence of prostate cancer in smokers given supplements of 50 mg of synthetic a-tocopherol (equivalent to 25 mg of RRR-a-tocopherol) daily (21). Because of these findings a large randomized,placebo-controlled intervention study is currently being conducted to examine the effect of a-tocopherol supplementation on prostate cancer risk (22).

Cataracts:Cataracts appear to be formed by the oxidation of proteins in thelens of the eye, which may be prevented by antioxidants such as a-tocopherol. To date, ten observational studies have examined the association between vitamin E consumption and the incidence and severity of cataracts. Of these studies, five found increased vitamin E intake to be associated with protection from cataracts, while five reported no association (23,24). A recent intervention trial of a daily antioxidant supplement containing 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of b-carotene in 4,629 men and women found that the antioxidant supplement was no different than a placebo in its effects on the development and progression of age-related cataracts over a 7-year period (25). Another intervention trial found that a daily supplement of 50 mg of synthetic a-tocopherol daily (equivalent to 25 mg of RRR- a-tocopherol) did not alter the incidence of cataract surgery in male smokers (26). Presently, the relationship between vitamin E intake and the development of cataracts requires further clarification before specific recommendations can be made.

Immune Function: a-Tocopherol has been shown to enhance specific aspects of the immune response that appear to decline as people age. For example, 200 mg of synthetic a-tocopherol (equivalent to 100 mg of RRR-a-tocopherol) daily for several months increased the formation of antibodies in response to hepatitis B vaccine and tetanus vaccine in elderly adults (27). Whether a-tocopherol associated enhancements in the immune response actually translate to increased resistance to infections such as the flu (influenza virus) in older adults remains to be determined (28).

DISEASE TREATMENT

Cardiovascular diseases: Observational studies have suggested that supplemental a-tocopherol might have value in the treatment of cardiovascular disease. For example, a small observational study of men who had previously undergone a coronary artery bypass graft found a reduction in the progression of coronary artery atherosclerosis by angiography in those men who took at least 100 IU of a-tocopherol (67 mg of RRR-a-tocopherol) daily (29). Arandomized, placebo-controlled intervention trial in Great Britain (the CHAOS study) found that supplementing heart diseasepatients with either 400 or 800 IU of synthetic a-tocopherol (equivalent to 268 or 536 mg of RRR-a-tocopherol) for an average of 18 months resulted in a dramatic 77% reduction in nonfatal heart attacks. However, total deaths from heart disease were not significantly reduced (30). Chronic renal dialysis patients are at much greater risk of dying from cardiovascular disease than the general population, and there is evidence that they are also under increased oxidative stress. Supplementation of renal dialysis patients with 800 IU of natural a-tocopherol (536 mg of RRR-a-tocopherol) for an average of 1.4 years resulted in a significantly reduced risk of heart attack compared to placebo (31). In contrast, three other intervention trials failed to find significant risk reductions with a-tocopherol supplementation. One study, which was designed mainly to examine cancer prevention, found that 50 mg of synthetic a-tocopherol daily (equivalent to 25 mg of RRR-a-tocopherol) resulted in a non-significant decrease in nonfatal heart attacks in those participants who had had previous heart attacks (32) . However, two other large trials found that daily supplements of 400 IU of natural a-tocopherol (equivalent to 268 mg RRR-a-tocopherol) and 300 mg of synthetic a-tocopherol (equivalent to 150 mg of RRR-a-tocopherol) in individuals with evidence of cardiovascular disease (previous heart attack, stroke, or evidence of vascular disease) did not significantly change the risk of a subsequent heart attack or stroke (33,34). The results of several other large intervention trials, which are presently in progress may clarify the role of a-tocopherol supplementation in the treatment of cardiovascular disease.

A more thorough discussion of the complex issues involved in analyzing the results of recent trials of vitamin E in heart disease can be found in the Fall/Winter 1999 issue of the Linus Pauling Institute Newsletter: Fish Oil, Vitamin E, Genes, Diet, and CHAOS. For a discussion of some of the limitations of the HOPE study see the article, Vitamin E: Hope or Hopeless,in the Spring/Summer 2000 issue of the Linus Pauling Institute Newsletter.

Diabetes mellitus: a-Tocopherol supplementation of individuals with diabeteshas been proposed because diabetes appears to increase oxidative stress and because cardiovascular complications (heart attack and stroke) are among the leading causes of death in diabetics. A recent study found a biochemical marker of oxidative stress to be elevated in diabetic individuals (35). Supplementation with 600 mg of synthetic a-tocopherol daily (equivalent to 300 mg of RRR-a-tocopherol) for 14 days resulted in a reduction in the oxidative stress marker. Studies of the effect of a-tocopherol supplementation on blood glucose control have been contradictory. One study reported improved control of blood glucose levels with supplementation of only 100 IU of synthetic a-tocopherol daily (equivalent to 45 mg RRR-a-tocopherol) (36), while studies using 900 to 1,600 IU of synthetic a-tocopherol daily (equivalent to 405 to 720 mg RRR-a-tocopherol) found either minimal or no improvement, respectively (37,38). Although there is reason to suspect that a-tocopherol supplementation may be beneficial for individuals with diabetes, evidence from well-controlled clinical trials is lacking.

Dementia (impaired cognitive function): The brain is particularly vulnerable to oxidative stress, which is thought to play a role in the pathology of neurodegenerative diseases, such as Alzheimer’s disease(39). In a large placebo-controlled intervention trial, supplementation of individuals who had moderate neurological impairment with 2,000 IU of synthetic a-tocopherol daily for two years (equivalent to 900 mg/day of RRR-a-tocopherol) resulted in a significant slowing of the progression of Alzheimer’s dementia(40). After Alzheimer’s disease, vascular dementia (dementia resulting from strokes) is the most common cause of dementia in the U.S. A case-control study examining risk factors for vascular dementia in elderly Japanese-American men found that supplemental vitamin E and vitamin C intake was associated with a significantly decreased risk of vascular and other types of dementia, but not Alzheimer’s dementia (41). Among those without dementia, vitamin E supplement use was associated with better scores on cognitive tests. Although these findings are promising, further studies are required to determine the role of a-tocopherol supplementation in the treatment of Alzheimer’s disease and other types of dementia.

SOURCES

Food sources: Major sources of a-tocopherol in the American diet include vegetable oils (olive, sunflower, safflower oils), nuts, whole grains, and green leafy vegetables. All eight forms of vitamin E (a, b, g, d tocopherols and tocotrienols) occur naturally in foods, but in varying amounts. Before the body’s preference for a-tocopherol was clarified, the vitamin E content of food was often expressed as mg of a-tocopherol equivalents or a-TE. Presently most food composition tables and databases provide vitamin E content information only in terms of a-TE, rather than as mg of a-tocopherol. If you wish to check foods you eat frequently for their nutrient content, search the USDA food composition database. A rough approximation of the a-tocopherol content in foods can be calculated by multiplying the mg of a-TE by 0.8 (3).

Example: 2.0 mg a-TE x 0.8 = 1.6 mg a-tocopherol.

The a- and g-tocopherol values in the table below were measured in foods, rather than calculated from a-TE.

Food

Serving

a-tocopherol (mg)

g-tocopherol (mg)

Olive oil

1 tablespoon

1.6

0.1

Soy oil

1 tablespoon

1.0

10.8

Corn oil

1 tablespoon

1.5

8.2

Canola oil

1 tablespoon

2.9

0.6

Safflower oil

1 tablespoon

4.6

0.1

Sunflower oil

1 tablespoon

6.6

0.7

Almonds

1 ounce

12.8

0.5

Hazelnuts

1 ounce

6.1

0.03

Peanuts

1 ounce

3.2

2.4

Spinach

1/2 cup, raw chopped

1.7

0

Carrots

1/2 cup, raw chopped

0.3

0

Avocado (Haas)

1 medium

3.3

1.2

Supplements:

a-Tocopherol: The average intake of a-tocopherol from food in the U.S. is approximately 9 mg daily for men and 6 mg daily for women, well below the recently revised RDA of 15 mg/day of RRR-a-tocopherol (3). Many scientists believe it is difficult for an individual to consume more than 15 mg/day of a-tocopherol from food alone, without also increasing fat intake above recommended levels (greater than 30% of total caloric intake). All a-tocopherol in food is the form of the isomer, RRR-a-tocopherol. The same is not always true for supplements. Vitamin E supplements generally contain from 100 IU to 1000 IU of a-tocopherol. Supplements made from entirely natural sources contain only RRR-a-tocopherol (also labeled d-a-tocopherol). RRR-a-tocopherol is the isomer preferred for use by the body, making it the most bioavailableform of a-tocopherol. Synthetic a-tocopherol, which is often found in food additives and nutritional supplements, is usually labeled all-rac-a-tocopherol or dl-a-tocopherol, meaning that all eight isomers of a-tocopherol are present in the mixture. Because some isomers of a-tocopherol present in all-rac-a-tocopherol are not usable by the body, synthetic a-tocopherol is less bioavailable and only about half as potent. To calculate the number of mg of bioavailable a-tocopherol present in a supplement, use the following formulas:

g-Tocopherol: g-Tocopherol supplements and mixed tocopherol supplements are also commercially available (42). The amounts of a- and g-tocopherol vary in mixed tocopherol supplements, so it is important to read the label to determine the amount of each tocopherol present in the supplement.

SAFETY

Toxicity: Few side effects have been noted in adults taking supplements of less than 2,000 mg of a-tocopherol daily (RRR- or all-rac-a-tocopherol). However, most studies of toxicity or side effects of a-tocopherol supplementation have lasted only a few weeks to a few months, and side effects occurring as a result of long-term a-tocopherol supplementation have not been adequately studied. The most worrisome possibility is that of impaired blood clotting resulting in an increased likelihood of hemorrhage in some individuals. In addition to setting the new RDA for a-tocopherol in April of 2000, the Food and Nutrition Board of the Institute of Medicine also set a UL (tolerable upper intake level) for a-tocopherol supplements, citing the avoidance of hemorrhage as the basis for the upper limit. The Board felt that a UL of 1,000 mg daily of a-tocopherol of any form (equivalent to1,500 IU of RRR-a-tocopherol or 1,100 IU of all-rac-a-tocopherol) would be the highest dose unlikely to result in hemorrhage in almost all adults (3). Although only certain isomers of a-tocopherol are retained in the circulation, all forms are absorbed and the liver must break them down and eliminate them. The rationale that any form of of a-tocopherol (natural or synthetic) that can be absorbed potentially could have adverse effects is the basis for a UL that refers to all forms of a-tocopherol. Because hemorrhage is a potentially life threatening condition, the Linus Pauling Institute also recommends that individuals do not exceed 1,000 mg of a-tocopherol/day. Premature infants appear to be especially vulnerable to adverse effects of a-tocopherol supplementation, which should be used only under controlled supervision by a pediatrician. Some physicians recommend that high-dose vitamin E supplementation be discontinued 1 month before elective surgery to decrease the risk of hemorrhage (42).

Drug interactions: Individuals on anticoagulant therapy (blood thinners) or individuals who are vitamin K deficient should not take a-tocopherol supplements without close medical supervision because of the increased risk of hemorrhage (3). A number of medications may decrease the absorption of vitamin E, including cholestyramine, colestipol, isoniazid, mineral oil, orlistat, sucralfate, and the fat substitute, olestra. Anticonvulsant drugs such as phenobarbitol, phenytoin, or carbamazepine may decrease plasma levels of vitamin E (3,42).

THE LINUS PAULING INSTITUTE RECOMMENDATION

Researchers at the Linus Pauling Institute feel there exists credible evidence that a dose of 200 mg of natural source d- or RRR-a-tocopherol daily for adults may help protect against chronic diseases like heart disease, stroke, and some types of cancer. The amount of a-tocopherol required for such beneficial effects appears to be much greater than that which could be achieved through diet alone (SeeSources). A supplement containing the equivalent of 200 mg/day of RRR-a-tocopherol is well below the upper level of 1,000 mg considered safe for most adults, but high enough to saturate plasma levels and systematically increase a-tocopherol levels in tissues. a-Tocopherol supplements are unlikely to be absorbed unless taken with food.

Older adults (65 years and older): The Linus Pauling Institute’s recommendation of 200 mg/day of natural source d- or RRR-a-tocopherol is also appropriate for generally healthy older adults, who are at higher risk for chronic diseases like heart disease, stroke, cataracts, and cancer.

Ford ES, Sowell A. Serum alpha-tocopherol status in the United States population: findings from the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 1999;150(3):290-300. (PubMed)